A study to evaluate S241656 alone or in combination in participants with selected myeloid malignancies

Prior treatment

• Prior therapy and washout: - Failure to recover to ≤ Grade 1 from previous toxicities (except Grade 2 neuropathy/alopecia). - Major surgery within 4 weeks. - Any anticancer therapy within 2 weeks or 5 half-lives (28 days for biologics). Cytoreduction with hydroxyurea or cytarabine is permitted. - Prior use of experimental KRAS/BRAF/MEK/ERK inhibitors (prior FLT3 inhibitors are permitted).

Other illness

• Medical conditions and infectious diseases: - Uncontrolled infections (human immunodeficiency virus (HIV)/hepatitis B virus (HBV)/hepatitis C virus (HCV) permitted only if viral load is undetectable/controlled and specific cluster of differentiation 4 (CD4)+ criteria are met). - Malabsorption, Crohn’s, or chronic vomiting that impacts oral drug absorption. - History/risk of retinal vein occlusion (RVO), glaucoma, or hyper-viscosity syndromes. - Other active malignancy requiring systemic therapy within 2 years (except non-melanoma skin cancer or localized/cured tumors).

Lab values

• General and excluded diagnoses: - Allergy: Known hypersensitivity to S241656 or posaconazole (Part 1B). - Pregnancy: Pregnant or breastfeeding; positive serum pregnancy test for WOCBP. - Acute promyelocytic leukemia (French-American-British [FAB] M3 classification), MPN, mixed/ambiguous lineage, histiocytic/dendritic cell neoplasms - AML with isolated extramedullary disease (no marrow/blood involvement) (WHO 2022). - Active Central Nervous System (CNS) disease (by cytologic or radiographic evidence)
• Cardiovascular and coagulation: - Stroke, myocardial infarction (MI), unstable angina, or acute coronary syndrome within 6 months. - Congestive heart failure (New York Heart Association (NYHA) ≥ II), clinically significant cardiac arrhythmias according to the investigator’s judgement (e.g., ventricular tachycardia), complete left bundle branch block and high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II- and third-degree AV block) - Fridericia-corrected QT interval (QTcF) > 470 msec or history of Torsades de pointes. - Disseminated intravascular coagulation (DIC), significant coagulopathy according to the investigator’s judgement, or uncontrolled bleeding
• Prohibited concomitant medications - [CCI]: Must discontinue 7–14 days prior to Cycle 1 Day 1. - Gastric pH: Proton Pump Inhibitors (PPIs) and potassium-competitive acid blockers ≥ 7 days prior to Cycle 1 Day 1. - Substrates: breast cancer resistance protein (BCRP) sensitive substrate or with a narrow therapeutic index (NTI), [CCI] with a NTI and P-gp sensitive substrates or with a NTI - Supplements: All herbal preparations/supplements are prohibited.

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Investigator-assessed life expectancy of ≥ 3 months
• Able and willing to comply with requirements of the study protocol
• Women of childbearing potential (WOCBP) must use a highly effective method of birth control as specified within the protocol
• Male participants with WOCBP partners must use a condom as specified within the protocol
• Disease-specific inclusion by study part: Parts 1 (Dose Escalation and DDI): Relapsed/Refractory (R/R), pathologically confirmed AML, MDS/AML, or CMML (WHO 2022/ICC classifications). Must have failed ≥ 1 approved standard therapy and have no other approved standard options.
• Documented genetic characterization of the disease as per local practice.
• Clinical and laboratory thresholds: - Cytoreduction: white blood cell (WBC) < 25 × 10⁹/L (hydroxyurea/cytarabine/leukapheresis allowed). - Renal: creatinine clearance (CrCl) ≥ 60 mL/min (Cockcroft-Gault). - Hepatic: aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN) (5 × if leukemic); Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for Gilbert’s syndrome).